tbuckley/cabot-search huggingface dataset:
Parallel single-cell and bulk transcriptome analyses reveal key features of the gastric tumor microenvironment
Authors: Boxi Kang, Jordi Camps, Biao Fan, Hongpeng Jiang, Mahmoud M. Ibrahim, Xueda Hu, Shishang Qin, Dennis Kirchhoff, Derek Y. Chiang, Shan Wang, Yingjiang Ye, Zhanlong Shen, Zhaode Bu, Zemin Zhang, Helge G. Roider
Journal: Genome biology (2022)

Abstract Background The tumor microenvironment (TME) has been shown to strongly influence treatment outcome for cancer patients in various indications and to influence the overall survival. However, the cells forming the TME in gastric cancer have not been extensively characterized. Results We combine bulk and single-cell RNA sequencing from tumors and matched normal tissue of 24 treatment-naïve GC patients to better understand which cell types and transcriptional programs are associated with malignant transformation of the stomach. Clustering 96,623 cells of non-epithelial origin reveals 81 well-defined TME cell types. We find that activated fibroblasts and endothelial cells are most prominently overrepresented in tumors. Intercellular network reconstruction and survival analysis of an independent cohort imply the importance of these cell types together with immunosuppressive myeloid cell subsets and regulatory T cells in establishing an immunosuppressive microenvironment that correlates with worsened prognosis and lack of response in anti-PD1-treated patients. In contrast, we find a subset of IFNγ activated T cells and HLA-II expressing macrophages that are linked to treatment response and increased overall survival. Conclusions Our gastric cancer single-cell TME compendium together with the matched bulk transcriptome data provides a unique resource for the identification of new potential biomarkers for patient stratification. This study helps further to elucidate the mechanism of gastric cancer and provides insights for therapy.
Long-term outcomes with nivolumab plus ipilimumab versus sunitinib in first-line treatment of patients with advanced sarcomatoid renal cell carcinoma
Authors: Brian I Rini, Sabina Signoretti, Toni K Choueiri, David F McDermott, Robert J Motzer, Saby George, Thomas Powles, Frede Donskov, Scott S Tykodi, Sumanta K Pal, Saurabh Gupta, Chung-Wei Lee, Ruiyun Jiang, Nizar M Tannir
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Patients with advanced renal cell carcinoma with sarcomatoid features (sRCC) have a poor prognosis and limited therapeutic options. First-line nivolumab plus ipilimumab (NIVO+IPI) provided efficacy benefits over sunitinib (SUN) in patients with intermediate/poor-risk sRCC at 42 months minimum follow-up in the phase 3 CheckMate 214 trial. In this exploratory post hoc analysis, we report clinical efficacy of NIVO+IPI in sRCC after a minimum follow-up of 5 years. Methods In CheckMate 214, patients with clear cell advanced RCC were randomized to NIVO 3 mg/kg plus IPI 1 mg/kg every 3 weeks (four doses), then NIVO 3 mg/kg every 2 weeks versus SUN 50 mg once daily (4 weeks; 6-week cycles). Randomized patients with sRCC were identified via independent central pathology review of archival tumor tissue or histological classification per local pathology report. Overall survival (OS), as well as progression-free survival (PFS) and objective response rate (ORR) per independent radiology review using Response Evaluation Criteria in Solid Tumors V.1.1, were evaluated in all International Metastatic Renal Cell Carcinoma Database Consortium intermediate/poor-risk sRCC patients and by baseline tumor PD-L1 expression level (≥1% vs &lt;1%). Safety outcomes are reported using descriptive statistics. Results In total, 139 patients with intermediate/poor-risk sRCC were identified (NIVO+IPI, n=74; SUN, n=65). At 5 years minimum follow-up, more patients remained on treatment with NIVO+IPI versus SUN (12% vs zero). Efficacy benefits with NIVO+IPI versus SUN were maintained with median OS of 48.6 vs 14.2 months (HR 0.46), median PFS of 26.5 vs 5.5 months (HR 0.50), and ORR 60.8% vs 23.1%. In addition, median duration of response was longer (not reached vs 25.1 months), and more patients had complete responses (23.0% vs 6.2%) with NIVO+IPI versus SUN, respectively. Efficacy was better with NIVO+IPI versus SUN regardless of tumor PD-L1 expression, but the magnitude of OS, PFS, and ORR benefits with NIVO+IPI was greater for sRCC patients with tumor PD-L1 ≥1%. No new safety signals emerged in either arm with longer follow-up. Conclusions Among patients with intermediate/poor-risk sRCC, NIVO+IPI maintained long-term survival benefits and demonstrated durable and deep responses over SUN at minimum follow-up of 5 years, supporting NIVO+IPI as a preferred first-line therapy in this population. Trial registration number NCT02231749 .
Black women’s menstrual and reproductive health: a critical call for action in the UK
Authors: Danielle Perro, Holly Seglah, Victoria Abrahams, Annalise Weckesser, Véronique A S Griffith
Journal: BMJ (2022)

Inadequate menstrual health education in the UK contributes to delayed and poor treatment for menstrual related disorders, such as endometriosis and uterine fibroids, many of which severely impact quality of life. 1 Systemic racism and unconscious bias in healthcare 2 3 compound barriers to Black women receiving the menstrual healthcare they need.Guided by preliminary results of the ongoing Black Women's Reproductive Health (BWRH) project, 4 we offer key recommendations to support Black women's menstrual and reproductive health.
Alcohol related disorders among elite male football players in Sweden: nationwide cohort study
Authors: Peter Ueda, Björn Pasternak, Henrik Svanström, Carl-Emil Lim, Martin Neovius, Magnus Forssblad, Jonas F Ludvigsson, Manzur Kader
Journal: BMJ (2022)

To assess whether male elite football players are at increased risk of alcohol related disorders compared with men from the general population, and whether such an increased risk would vary on the basis of calendar year of the first playing season in the top tier of competition, age, career length, and goal scoring abilities.Nationwide cohort study.Sweden, 1924-2020.6007 male football players who had played in the Swedish top division, Allsvenskan, from 1924 to 2019 and 56 168 men from the general population matched to players based on age and region of residence.Primary outcome was alcohol related disorders (diagnoses recorded in death certificates, during hospital admissions and outpatient visits, or use of prescription drugs for alcohol addiction); secondary outcome was disorders related to misuse of other drugs.During follow-up up to 31 December 2020, 257 (4.3%) football players and 3528 (6.3%) men from the general population received diagnoses of alcohol related disorders. In analyses accounting for age, region of residence, and calendar time, risk of alcohol related disorders was lower among football players than among men from the general population (hazard ratio 0.71, 95% confidence interval 0.62 to 0.81). A reduced risk of alcohol related disorders was observed for football players who played their first season in the top tier in the early 1960s and later, while no significant difference versus men from the general population was seen in the risk for football players from earlier eras. The hazard ratio was lowest at around age 35 years, and then increased with age; at around age 75 years, football players had a higher risk of alcohol related disorders than men from the general population. No significant association was seen between goal scoring, number of games, and seasons played in the top tier and the risk of alcohol related disorders. Risk of disorders related to other drug misuse was significantly lower among football players than the general population (hazard ratio 0.22, 95% confidence interval 0.15 to 0.34).In this nationwide cohort study, male football players who had played in the Swedish top tier of competition had a significantly lower risk of alcohol related disorders than men from the general population.
Measuring human energy expenditure: public health application to counter inactivity
Authors: Glenn A Gaesser, David C Poole, Siddhartha S Angadi
Journal: BMJ (2022)

This article discusses the use of indirect calorimetry for the measurement of human energy expenditure. Quantification of energy expenditure during low efficiency walking (as depicted in the Monty Python sketch The Ministry of Silly Walks) is presented as an example of how physical activity recommendations could be met by exchanging ~11 minutes per day of normal walking with low efficiency walking—without requiring any further time commitment.
Quantifying the benefits of inefficient walking: Monty Python inspired laboratory based experimental study
Authors: Glenn A Gaesser, David C Poole, Siddhartha S Angadi
Journal: BMJ (2022)

To compare the rate of energy expenditure of low efficiency walking with high efficiency walking.Laboratory based experimental study.United States.13 healthy adults (six women, seven men) with no known gait disorder, mean (±standard deviation) age 34.2±16.1 years, height 174.2±12.6 cm, weight 78.2±22.5 kg, and body mass index 25.6±6.0.Participants performed three, five minute walking trials around an indoor 30 m course. The first trial consisted of walking at a freely chosen walking speed in the participant's usual style. The next two trials consisted of low efficiency walks in which participants were asked to duplicate the walks of Mr Teabag and Mr Putey (acted by John Cleese and Michael Palin, respectively) in the legendary Monty Python Ministry of Silly Walks (MoSW) skit that first aired in 1970. Distance covered during the five minute walks was used to calculate average speed. Ventilation and gas exchange were collected throughout to determine oxygen uptake (V̇O2; mL O2/kg/min) and energy expenditure (EE; kcal/kg/min; 1 kcal=4.18 kJ), reported as mean±standard deviation.V̇O2 and EE.V̇O2 and EE were about 2.5 times higher (P<0.001) during the Teabag walk compared with participants' usual walk (27.9±4.8 v 11.3±1.9 mL O2/kg/min; 0.14±0.03 v 0.06±0.01 kcal/kg/min), but were not different during the Putey walk (12.3±1.8 mL/kg/min; 0.06±0.01 kcal/kg/min). Each minute of Teabag walking increased EE over participants' usual walking by an average of 8.0 kcal (range 5.5-12.0) in men and by 5.2 kcal (range 3.9-6.2) in women, and qualified as vigorous intensity physical activity (>6 resting metabolic equivalents).For adults with no known gait disorder who average approximately 5000 steps/day, exchanging about 22%-34% of their daily steps with higher energy, low efficiency walking in Teabag style-requiring around 12-19 min-could increase daily EE by 100 kcal. Adults could achieve 75 minutes of vigorous intensity physical activity per week by walking inefficiently for about 11 min/day. Had an initiative to promote inefficient movement been adopted in the early 1970s, we might now be living among a healthier society. Efforts to promote higher energy-and perhaps more joyful-walking should ensure inclusivity and inefficiency for all.
Dose–response correlation for CAR-T cells: a systematic review of clinical studies
Authors: Anand Rotte, Matthew J Frigault, Ayub Ansari, Brad Gliner, Christopher Heery, Bijal Shah
Journal: Journal for ImmunoTherapy of Cancer (2022)

The potential of chimeric antigen receptor (CAR) T cells to successfully treat hematological cancers is widely recognized. Multiple CAR-T cell therapies are currently under clinical development, with most in early stage, during which dose selection is a key goal. The objective of this review is to address the question of dose-dependent effects on response and/or toxicity from available CAR-T cell clinical trial data. For that purpose, systematic literature review of studies published between January 2010 and May 2022 was performed on PubMed and Embase to search clinical studies that evaluated CAR-T cells for hematological cancers. Studies published in English were considered. Studies in children (age &lt;18 years), solid tumors, bispecific CAR-T cells and CAR-T cell cocktails were excluded. As a result, a total of 74 studies met the inclusion criteria. Thirty-nine studies tested multiple dose levels of CAR-T cells with at least &gt;1 patient at each dose level. Thirteen studies observed dose-related increase in disease response and 23 studies observed dose-related increase in toxicity across a median of three dose levels. Optimal clinical efficacy was seen at doses 50–100 million cells for anti-CD19 CAR-T cells and &gt;100 million cells for anti-BCMA CAR-T cells in majority of studies. The findings suggest, for a given construct, there exists a dose at which a threshold of optimal efficacy occurs. Dose escalation may reveal increasing objective response rates (ORRs) until that threshold is reached. However, when ORR starts to plateau despite increasing dose, further dose escalation is unlikely to result in improved ORR but is likely to result in higher incidence and/or severity of mechanistically related adverse events.
Everything causes cancer? Beliefs and attitudes towards cancer prevention among anti-vaxxers, flat earthers, and reptilian conspiracists: online cross sectional survey
Authors: Sonia Paytubi, Yolanda Benavente, Alexandra Montoliu, Gemma Binefa, Maria Brotons, Raquel Ibáñez, Cristian Ochoa, Paula Peremiquel-Trillas, Beatriz Serrano, Noémie Travier, Laia Alemany, Laura Costas
Journal: BMJ (2022)

To evaluate, using an online non-probability sample, the beliefs about and attitudes towards cancer prevention of people professing vaccination scepticism or conspiracy theories.Cross sectional survey.Data collected mainly from ForoCoches (a well known Spanish forum) and other platforms, including Reddit (English), 4Chan (English), HispaChan (Spanish), and a Spanish language website for cancer prevention (mejorsincancer.org) from January to March 2022.Among 1494 responders, 209 were unvaccinated against covid-19, 112 preferred alternative rather than conventional medicine, and 62 reported flat earth or reptilian beliefs.Cancer beliefs assessed using the Cancer Awareness Measure (CAM) and Cancer Awareness Measure Mythical Causes Scale (CAM-MYCS) (both validated tools).Awareness of the actual causes of cancer was greater (median CAM score 63.6%) than that of mythical causes (41.7%). The most endorsed mythical causes of cancer were eating food containing additives or sweeteners, feeling stressed, and eating genetically modified food. Awareness of the actual and mythical causes of cancer among the unvaccinated, alternative medicine, and conspiracy groups was lower than among their counterparts. A median of 54.5% of the actual causes was accurately identified among each of the unvaccinated, alternative medicine, and conspiracy groups, and a median of 63.6% was identified in each of the three corresponding counterparts (P=0.13, 0.04, and 0.003, respectively). For mythical causes, medians of 25.0%, 16.7%, and 16.7% were accurately identified in the unvaccinated, alternative medicine, and conspiracy groups, respectively; a median of 41.7% was identified in each of the three corresponding counterparts (P<0.001 in adjusted models for all comparisons). In total, 673 (45.0%) participants agreed with the statement "It seems like everything causes cancer." No significant differences were observed among the unvaccinated (44.0%), conspiracist (41.9%), or alternative medicine groups (35.7%), compared with their counterparts (45.2%, 45.7%, and 45.8%, respectively).Almost half of the participants agreed that "It seems like everything causes cancer," which highlights the difficulty that society encounters in differentiating actual and mythical causes owing to mass information. People who believed in conspiracies, rejected the covid-19 vaccine, or preferred alternative medicine were more likely to endorse the mythical causes of cancer than their counterparts but were less likely to endorse the actual causes of cancer. These results suggest a direct connection between digital misinformation and consequent erroneous health decisions, which may represent a further preventable fraction of cancer.
Crumbs of comfort in this time of despair
Authors: Jennifer Rasanathan
Journal: BMJ (2022)

Crumbs of comfort in this time of despairJennifer Rasanathan head of scholarly comment It seems that there are more reasons to despair than ever in 2022.However, 40 years since the first Christmas issue of The BMJ, we aim to give you comfort, as health professionals struggle to cope with the unrelenting demands placed on health services.
Molecular Tweezers: Supramolecular Hosts with Broad-Spectrum Biological Applications
Authors: Hedieh Shahpasand-Kroner, Ibrar Siddique, Ravinder Malik, Gabriel R. Linares, Magdalena I. Ivanova, Justin Ichida, Tatjana Weil, Jan Münch, Elsa Sanchez-Garcia, Frank-Gerrit Klärner, Thomas Schrader, Gal Bitan
Journal: Pharmacological Reviews (2022)

Lysine-selective molecular tweezers (MTs) are supramolecular host molecules displaying a remarkably broad spectrum of biologic activities. MTs act as inhibitors of the self-assembly and toxicity of amyloidogenic proteins using a unique mechanism. They destroy viral membranes and inhibit infection by enveloped viruses, such as HIV-1 and SARS-CoV-2, by mechanisms unrelated to their action on protein self-assembly. They also disrupt biofilm of Gram-positive bacteria. The efficacy and safety of MTs have been demonstrated in vitro, in cell culture, and in vivo, suggesting that these versatile compounds are attractive therapeutic candidates for various diseases, infections, and injuries. A lead compound called CLR01 has been shown to inhibit the aggregation of various amyloidogenic proteins, facilitate their clearance in vivo, prevent infection by multiple viruses, display potent anti-biofilm activity, and have a high safety margin in animal models. The inhibitory effect of CLR01 against amyloidogenic proteins is highly specific to abnormal self-assembly of amyloidogenic proteins with no disruption of normal mammalian biologic processes at the doses needed for inhibition. Therapeutic effects of CLR01 have been demonstrated in animal models of proteinopathies, lysosomal-storage diseases, and spinal-cord injury. Here we review the activity and mechanisms of action of these intriguing compounds and discuss future research directions. <h3>Significance Statement</h3> Molecular tweezers are supramolecular host molecules with broad biological applications, including inhibition of abnormal protein aggregation, facilitation of lysosomal clearance of toxic aggregates, disruption of viral membranes, and interference of biofilm formation by Gram-positive bacteria. This review discusses the molecular and cellular mechanisms of action of the molecular tweezers, including the discovery of distinct mechanisms acting in vitro and in vivo, and the application of these compounds in multiple preclinical disease models.
Tumor-derived OBP2A promotes prostate cancer castration resistance
Authors: Ji-Hak Jeong, Shangwei Zhong, Fuzhuo Li, Changhao Huang, Xueyan Chen, Qingqing Liu, Shoujiao Peng, HaJeung Park, You Mie Lee, Jasreman Dhillon, Jun-Li Luo
Journal: The Journal of Experimental Medicine (2022)

Androgen deprivation therapy (ADT) is a systemic therapy for advanced prostate cancer (PCa); although most patients initially respond to ADT, almost all cancers eventually develop castration-resistant PCa (CRPC). Currently, most research focuses on castration-resistant tumors, and the role of tumors in remission is almost completely ignored. Here, we report that odorant-binding protein (OBP2A) released from tumors in remission during ADT catches survival factors, such as CXCL15/IL8, to promote PCa cell androgen-independent growth and enhance the infiltration of myeloid-derived suppressor cells (MDSCs) into tumor microenvironment, leading to the emergence of castration resistance. OBP2A knockdown significantly inhibits CRPC and metastatic CRPC development and improves therapeutic efficacy of CTLA-4/PD-1 antibodies. Treatment with OBP2A-binding ligand α-pinene interrupts the function of OBP2A and suppresses CRPC development. Furthermore, α-pinene–conjugated doxorubicin/docetaxel can be specifically delivered to tumors, resulting in improved anticancer efficacy. Thus, our studies establish a novel concept for the emergence of PCa castration resistance and provide new therapeutic strategies for advanced PCa.
A whole-brain monosynaptic input connectome to neuron classes in mouse visual cortex
Authors: Shenqin Yao, Quanxin Wang, Karla E. Hirokawa, Benjamin Ouellette, Ruweida Ahmed, Jasmin Bomben, Krissy Brouner, Linzy Casal, Shiella Caldejon, Andy Cho, Nadezhda I. Dotson, Tanya L. Daigle, Tom Egdorf, Rachel Enstrom, Amanda Gary, Emily Gelfand, Melissa Gorham, Fiona Griffin, Hong Gu, Nicole Hancock, Robert Howard, Leonard Kuan, Sophie Lambert, Eric Kenji Lee, Jennifer Luviano, Kyla Mace, Michelle Maxwell, Marty T. Mortrud, Maitham Naeemi, Chelsea Nayan, Nhan-Kiet Ngo, Thuyanh Nguyen, Kat North, Shea Ransford, Augustin Ruiz, Sam Seid, Jackie Swapp, Michael J. Taormina, Wayne Wakeman, Thomas Zhou, Philip R. Nicovich, Ali Williford, Lydia Potekhina, Medea McGraw, Lydia Ng, Peter A. Groblewski, Bosiljka Tasic, Stefan Mihalas, Julie A. Harris, Ali Cetin, Hongkui Zeng
Journal: Nature Neuroscience (2022)
Antibody-dependent cellular cytotoxicity against SARS-CoV-2 Omicron sub-lineages is reduced in convalescent sera regardless of infecting variant
Authors: Simone I. Richardson, Prudence Kgagudi, Nelia P. Manamela, Haajira Kaldine, Elizabeth M. Venter, Thanusha Pillay, Bronwen E. Lambson, Mieke A. van der Mescht, Tandile Hermanus, Sashkia R. Balla, Zelda de Beer, Talita R. de Villiers, Annie Bodenstein, Gretha van den Berg, Marizane du Pisanie, Wendy A. Burgers, Ntobeko A.B. Ntusi, Fareed Abdullah, Veronica Ueckermann, Theresa M. Rossouw, Michael T. Boswell, Penny L. Moore
Journal: Cell Reports Medicine (2022)

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron BA.4 and BA.5 variants caused major waves of infections. Here, we assess the sensitivity of BA.4 to binding, neutralization, and antibody-dependent cellular cytotoxicity (ADCC) potential, measured by FcγRIIIa signaling, in convalescent donors infected with four previous variants of SARS-CoV-2, as well as in post-vaccination breakthrough infections (BTIs) caused by Delta or BA.1. We confirm that BA.4 shows high-level neutralization resistance regardless of the infecting variant. However, BTIs retain activity against BA.4, albeit at reduced titers. BA.4 sensitivity to ADCC is reduced compared with other variants but with smaller fold losses compared with neutralization and similar patterns of cross-reactivity. Overall, the high neutralization resistance of BA.4, even to antibodies from BA.1 infection, provides an immunological mechanism for the rapid spread of BA.4 immediately after a BA.1-dominated wave. Furthermore, although ADCC potential against BA.4 is reduced, residual activity may contribute to observed protection from severe disease.